Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation.

We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F (1) and G (2), and cyclopiazonic acid (CPA) (3) as Notch activators. Pulicatin F (1) and (±)-pulicatin G were synthesized and their activities were evaluated. Notch activation of CPA (3) was investigated using Western blot and RT-PCR. CPA (3) increased protein level of HES1 and mRNA expression of HES1. Also, the expression of FMS-like tyrosine kinase 3 (FLT3), which was known to inhibit apoptosis, was also inhibited by CPA (3) addition. The Notch activation by CPA (3) and cytotoxicity against HL-60 were clearly canceled by addition of FK506, which is an inhibitor of calcineurin (CaN). In addition, it was revealed that CPA (3) induced apoptosis in HL-60 cells.

Noaoxazole, a new heat shock metabolite produced by thermotolerant Streptomyces sp. HR41.

The thermotolerant strain Streptomyces sp. HR41 was found to produce compound 1 only in a 45 °C culture, and not at the standard temperature. We previously designated this type of compound as a "heat shock metabolite" (HSM). NMR and MS analytical techniques were used to determine that the chemical structure of 1 comprised a methylated-oxazole ring and a linear chain moiety modified with a terminal amide group. Thus, 1 was shown to be a new curromycin analog, which we have designated noaoxazole (1). Compound 1 weakly activated Notch signal reporter activity without exhibiting cytotoxicity against assay cells at the same concentration.